Transporter Target Panel – Opti-Target™ Panel

Optivia’s Opti-TargetTM Transporter Services Panel,  consists of a wide variety of validated and novel transporter targets implicated in diseases, toxicity, and tissue targeting. Optivia offers both rapid, low-cost compound screening and comprehensive transporter profiling services to help you discover new classes of transporter-targeted therapeutics, and assist you in adopting a transporter-conscious strategy to improve drug response and safety.

Transporters are a class of over 400 membrane proteins that tightly regulate cross-membrane transport of nutrients, signaling molecules, and xenobiotics. Transporters play a critical role in drug response and toxicity, which has led to an increase in regulatory requests for assessing transporter mediated drug-drug interactions (DDIs). Aberrant transporter activity leads to or is associated with a variety of diseases, including cancer, neurological disorders, and diabetes. Therefore, rational design of transporter-targeting molecules represents an enormous opportunity for developing new therapeutic and diagnostic agents with novel mechanisms of action and improved efficacy and safety. This is demonstrated by an increasing number of approved and experimental drugs, as well as diagnostic agents acting on various transporters, such as sertraline (depression), canagliflozin (diabetes), ivacaftor (cystic fibrosis), lesinurad (gout), and 18F-FDG (cancer imaging).

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Opti-Target™ Panel: Transporters as Therapeutic, Toxicity, and Delivery Targets

TransporterPhysiological roleGeneMajor tissue distributionRelated disease/ADRExamples of interacting xenobioticsAvailable Species
ASBTBile acid uptakeSLC10A2ileum, kidney, biliary tract (apical)hypertriglycerimaemia, constipation, cholestatic liver diseases, NASH, primary bile acid malabsorptionelobixia, LUM001, SHP626, A4250Human
asc-1Amino acid transportSLC7A10brain, heart, placenta, skeletal muscle and kidneylearning and memory impairment, schizophreniaBMS-466442Human
ASCT2Amino acid transportSLC1A5lung, skeletal muscle, large intestine, kidney, testis, adipose tissue, tumor cellscancerGPNA, ketamineHuman
BSEPbile acid effluxABCB11LiverPFIC II, drug induced cholestasis and hepatitistroglitazone, rifampicin, benzbromarone, bosentan, cyclosporine AHuman, rat, dog
CNT1Nucleoside uptakeSLC28A1liver, kidney, small intestine, tumor cellscancer, infectious diseasesgemcitabine, cytarabine, azacitidine, zalcitabine, floxuridineHuman, rat
CNT2Nucleoside uptakeSLC28A2kidney (apical membrane), liver, heart, brain, placenta, pancreas, skeletal muscle, colon, rectum, small intestine, lymphocytes, tumor cellscancer, infectious diseasesribavirin, cladribine, didanosine, fludarabine, clofarabine, floxuridine, acacitidine, cladribineHuman, rat
CNT3Nucleoside uptakeSLC28A3pancreas, trachea, bone marrow, and mammary gland, intestine, brain, heart, prostrate, liver, tumor cellscancer, infectious diseasesgemcitabine, azacitidine, mercaptopurine, fludarabine, clofarabine, cladribine, floxuridineHuman, rat
DATNeurotransmissionSLC6A3brain (dopaminergic neurons), gutParkinson disease, Tourette syndrome, ADHD, addiction, major affective disoordersaltropane, vanoexerine, difluoropine, iometopane, DBL-583, GBR-12783, RTI-229, 11C-PE2IHuman
EAAT1NeurotransmissionSLC1A3brain (astrocytes, Bergmann glia), heart, skeletal muscle, placentaAlzheimer's disease, Huntington's disease, epilepsy, cerebellar ataxia type 7, schizophrenia, excitotoxicityRiluzole, l-trans-PDC, HIP-A, MPDC,TFB-TBOA, UCPH-101Human
EAAT2NeurotransmissionSLC1A2brain (astrocytes, Bergmann glia, neurons), liver, pancreasamyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, epilepsy, ischemia, schizophrenia, excitotoxicityDihydrokainic acid, SYM-2081, WAY-213613,l-trans-PDCHuman
ENT1Nucleoside transportSCL29A1heart, brain, mammary gland, erythrocytes and placenta, tumor cellscancer, infectious diseasesgemcitabine, 5-FU, zalcitabine, cytarabine, fludarabine,cladribine, azacitidine, pentostatin, decitabineHuman
ENT2Nucleoside transportSLC29A2skeletal muscle, liver, lung, placenta, brain, heart, kidney, ovarian tissues cancer, infectious diseaseszidovudine, zalcitabine, cytarabine, fludarabine, 5-FU, azacitidine, pentostatin, decitabine, cladribineHuman, rat
ENT4/PMATNucleoside transport and extrasynaptic reuptakeSLC29A4heart, brain, skeletal muscledepression, schizophrenia, bipolar disordertrazodone, decynium-22Human
GAT1NeurotransmissionSLC6A1central and peripheral neurons (GABAergic neurons)Epilepsy, schizophrenia, ADHDtiagabine, nipecotic acid, deramciclane, hyperforin, riluzole, SKF-89976A, NNC-711, SNAP-5114, CI-966Human
GAT2NeurotransmissionSLC6A13brain (meninges, ependyma, choroid plexus), retina, liver, kidneyEpilepsytiagabine, _-Alanine, nipecotic acid, riluzole, NNC05-2090, SKF 89976AHuman
GAT3NeurotransmissionSLC6A11brain (GABAergic neurons)Epilepsytiagabine, _-Alanine, nipecotic acid, riluzole, SKF 89976AHuman
GLYT1NeurotransmissionSLC6A9brain, retina, liver, spleen, kidney, pancreas, uterus, stomach, lung, placenta, intestine schizophreniaBitopertin, PF-04958242Human
NETNeurotransmissionSLC6A2brain (non adrenergic neuronal somata, axons, dendrites), peripheral nervous system, adrenal gland (chromaffin cells), placentadepression, orthostatic intolerance, anorexia nervosa, cardiovascular disorders, ADHDatomoxetine, reboxetine, desipramine,edivoxetine, viloxazine, maprotiline, nisoxetine, 123I-MIBG, 11C-HEDHuman
OATP1B1hepatic uptake of bilirubin and a variety of anionic drugsSLCO1B1liver (hepatocytes)statin-induced myopathy, hyperbilirubinemia, rotor syndromecyclosporine A, rifampicin, gemfibrozil, ritonavir/lopinavirHuman
OATP1B3hepatic uptake of bilirubin and a variety of anionic drugsSLCO1B3liver (hepatocytes)unconjugated hyperbilirubinemia, Rotor syndromecyclosporine A, rifampicin, ritonavir/lopinavirHuman
OCT2cation uptakeSLC22A2kidney, small intestine, lung, placenta, thymus, brain (neurons, blood-brain barrier), inner earcytotoxicity of cisplatin, oxaliplatin and picoplatincisplatin, oxaliplatin, picoplatinHuman, rat
OCT3cation uptake; extrasynaptic reuptakeSLC22A3heart, skeletal muscle, brain (neurons, glial cells, plexus choroideus), small intestine, liver, lung, kidney, urinary bladder, mammary gland, skin blood vesselsProstate cancer, coronary heart disease, obsessive compulsive disorder, depressionoxaliplatin, picoplatin, tetrabenazine, trazodoneHuman, rat
OCTN1ergothioneine uptakeSLC22A4kidney, intestine, spleen, heart, skeletal muscle, brain, mammary gland, thymus, prostate, airways, testis, eye, fetal liver, sperm, immune cellsRheumatoid arthritis, Crohn's diseaseverapamil, quinidine, propafenone, clofilumHuman
OCTN2carnitine uptakeSLC22A5skeletal muscle, kidney, prostate, lung, pancreas, heart, small intestine, adrenal gland, thyroid gland, liver, etc.Primary systemic carnitine deficiency, Crohn's diseaseverapamil, quinidine, valproate, cephaloridine, pyrilamineHuman
PCFTVitamin transportSLC46A1small intestine, choroid plexus, kidney (proximal tubule), liver (sinusoidal), placentahereditary folate malabsorption, cancermethotrxate, pemetrexed, bromosulfophthaleinHuman
PEPT1Peptide uptakeSLC15A1small intestine, kidney, pancreas, bile duct, liverinflammatory bowel diseaseglycylsarcosine, bestatin, y-ALA, cephalexin, valacyclovir, cyclacillin, losartanHuman
PEPT2Peptide uptakeSLC15A2apical surface of epithelial cells from kidney and choroid plexus; neurons, astrocytes (neonates), lung, mammary gland, spleen, enteric nervous systemlead exposurecefaclor, glycylsarcosine, bestatin, cephalexin, valacyclovir, losartanHuman
RFCVitamin transportSLC19A1ubiquitouscancermethotrxate, pemetrexed, tomudex,
edatrexate, bromosulfophthalein
SERTNeurotransmissionSCL6A4brain, peripheral nervous system, placenta, epithelium cells, plateletsanxiety, depression, autism gastrointestinal disorders, premature ejaculation, obesity, schizophrenia OCDsertraline, fluvoxamine, fluoxetine, citalopram, zimelidine, dapoxetine, paroxetine, escitalopram, 123I-ADAMHuman
SGLT2Glucose transportSLC5A2kidney, brain, liver, heart muscle, thyroid, salivary glandsType II Diabetes, familial renal glucosuriacanagliflozin, dapagliflozin, empagliflozin, tofogliflozin, ipragliflizin, remogliflozin, sotagliflozin, ertugliflozinHuman
SNAT1Amino acid transportSLC38A1brain, retina, heart, placenta, adrenal glandSuicidal behavior, cancerMeAIBHuman
SNAT2Amino acid transportSLC38A2ubiquitousSchizophrenia, cancerMeAIBHuman
THTR1Vitamin transportSLC19A2ubiquitousthiamine-responsive megaloblastic anemia syndromefedratinib, amprolium, pyrithiamine, oxythiamineHuman
THTR2Vitamin transportSLC19A3ubiquitousbiotin-responsive basal ganglia disease, Wernicke's encephalopathyfedratinib, amprolium, pyrithiamine, oxythiamineHuman
URAT1Uric acid reneal tubular reabsorptionSLC22A12kidneyrenal hypo-uricemia, goutLesinurad, RDEA3170, KUX-1151, benzbromaroneHuman
xCTAmino acid transport and neurotransmissionSLC7A11macrophages, brain, retinal pigment cells, liver, kidney, tumor cellscancer, epilepsy, neurodegenerative diseasessulfasalazine, erastin, BAY-94-9392, BMAAHuman

Transporter-Targeting Strategies and Examples

Transporters As Therapeutic Targets

Many transporters are important modulators of the trafficking and homeostasis of signaling molecules and nutrients. Thus, these transporter proteins themselves represent attractive targets in the treatment of various diseases. Therapeutic intervention of such transporters, either through inhibition or enhancement of activities, has produced numerous drugs. For instance, neurotransmitter reuptake transporters, such as SERTDAT, NET, and GATs, are classical targets of many blockbuster drugs that treat mental and neurological disorders, including depression, schizophrenia, epilepsy, and ADHD. Additionally,SGLT2 is the target of the diabetes drug canagliflozin, CFTR is the target of ivacaftor for treating cystic fibrosis, NPC1 is the target of the cholesterol-lowering drug ezetimibe, and URAT1 is the target of the gout drug lesinurad. Many novel transporter-targeting approaches are also under extensive investigation.  Some examples include blocking tumor growth through inhibiting nutrient/amino acid transporters (such as GLUTs, MCTs, ASCT2, and ATB0,+), controlling cellular oxidative stress through targeting xCT, treating schizophrenia by inhibiting asc-1 or Glyt1/Glyt2, and reducing bile acid reabsorption by blocking ASBT.  Most recently, evidence emerged for preventing virus cellular entry by blocking their transporter-docking mechanism (e.g. HBV-NTCP, ebola-NPC1).

Transporters As Toxicity Targets

Numerous genetic diseases are known to be caused by the aberrant activities of transporters playing key roles in physiological processes [4,6]. Therefore, the unexpected interactions of drugs with these transporters can lead to serious adverse effects. For example, neurotoxins (e.g. BMAA, ODAP) that inhibit glutamate transporters (e.g., EAATs and xCT) in the brain can lead to fetal acute brain damage and chronic neurological diseases. Drugs such as troglitazone and benzbromarone that inhibit hepatic bile salt transporters (BSEP and NTCP) ) are associated with cholestasis/hepatitis.  Recent studies using the JAK2 inhibitor fedratinib had the off-target effect of blocking the thiamine transporters THTR1 and THTR2, leading  to encephalopathy.

On the other hand, a less recognized effect is the involvement of transporters in the induction of drug toxicity due to undesired drug accumulation in organs such as kidney and liver. For instance, certain platinum drugs induce severe nephrotoxicity as a result of unwanted platinum accumulation in the kidney due to uptake by OCT2, which could potentially be prevented by addition of specific OCT2 inhibitors. Using similar strategies, it should be possible to decrease the toxicity of numerous marketed drugs that currently show undesirable accumulation in various tissues and organs, including heart, liver, and brain.

Transporters as Delivery Targets

Finally, since many transporters are tissue-specific/tissue-enriched (e.g. OATP1B1 in liver, OCT2 in kidney) or dysregulated in diseases (e.g. GLUT1 and ASCT2 in cancer, DAT in Parkinson’s), transporters can provide novel ways to achieve efficient and targeted intracellular delivery of drugs and imaging agents. Transporter-targeting approaches can be particularly attractive for intracellular drug delivery or prodrug designs as they circumvent the formidable challenge of endosomal escape faced by receptor-mediated endocytosis. One example comes from the class of nucleoside analog drugs (e.g. gemcitabine, 5-FU, zidovudine). These drugs rely on nucleoside transporters CNTs/ENTs for efficient cellular uptake. Therefore, expression levels of these transporters are an important determinant of treatment efficacy. Additional examples include: Lipid lowering statins which exploit OATP1B1/OATP1B3 for liver targeting, the anti-cancer drugs methotrexate and pemetrexed which utilize the vitamin transporters PCFT and RFC for tumor targeting, and several intestinal transporters that have been targeted in prodrug design for improving bioavailability (e.g. PEPT1/valacyclovir, MCT1/gabapentin enacarbil and ASBT/CDCA-glu-gabapentin).Transporters are also important targets for diagnostic imaging. The most successful PET imaging probe, 18F-FDG, is transported by GLUT1, a glucose transporter up-regulated in many cancers; several other cancer imaging probes also target transporters that are enriched in tumors (e.g. NET/123I-MIBG, LAT1/18F-FET, xCT/BAY-94-9392). In addition to tumor imaging, several probes (e.g., 11C-PE2I, 11C-HED ,123 I-ADAM and 18F-FBT) targeting transporters (such as NETDATSERT, VMAT and VAChT) are under development for detecting various neurological disorders, diabetes, and cardiovascular diseases. Similar to the GPCR targets that changed the pharmaceutical industry 25 years ago, membrane transporters represent enormous potential as therapeutic and diagnostic targets for various diseases.

Transporters As Targets Resources

Membrane transporters in drug development

SLC transporters as therapeutic targets: emerging opportunities

A Call for Systematic Research on Solute Carriers

The ABCs of membrane transporters in health and disease (SLC series): Introduction

Solute carriers as drug targets: Current use, clinical trials and prospective

What do drug transporters really do?

Possibilities of Cancer Chemotherapy Based on Transporter-Conscious Drug Design

Beyond the ITC White Paper: emerging sciences in drug transporters and opportunities for drug development

Bioparadigm SLC transporter database